A key pathogenic feature of type 2 diabetes is loss of the beta-cell compensation to the insulin resistance that occurs in this disease. The biochemical and molecular nature of this beta-cell failure are poorly known, in part because of lack of animal models that faithfully reproduce the natural history of the human disease. This proposal makes use of a newly developed rat model, the 60% pancreatectomy Zucker rat that incorporates the characteristic features of human adipogenic diabetes - obesity, insulin resistance, and hyperlipidemia. They are characterized by a 3-week period of relative normoglycemia after the partial pancreatectomy (compensation phase) that is followed by the onset of beta-cell dysfunction and mild hyperglycemia (decompensation phase). We will use this model to test the hypothesis of this application that enhanced then impaired a-cell anaplerosis and lipid partitioning are the mechanistic basis for the beta-cell compensation and subsequent beta-cell failure in these rats. A notable aspect of this application is it stems as a joint effort from the laboratories of Drs. Jack Leahy (Burlington, VT) and Marc Prentki (Montreal, Canada) who have complimentary research expertise in the fields of beta cell anaplerosis/lipid partitioning and the beta cell failure in rodent models of type 2 diabetes. Aim 1 will determine the cellular mechanisms and signaling pathways for beta-cell compensatory growth or loss of beta-cell mass in the 60% Px ZF rat model at different stages during the progression to diabetes. Aim 2 will test the hypothesis that the mechanism of beta-cell decompensation in the 60% Px ZF rat model is related to failure of compensatory enhanced anaplerosis and lipid signaling processes. Aim 3 will test the hypothesis that the beta-cell failure in 60% Px ZF rats is in part due to inadequate proinsulin synthesis relative to secretion. These studies will provide a better understanding of the molecular basis for beta-cell compensation and failure, and they hold considerable promise to provide targets for novel pharmaceutical approaches to the prevention or more effective treatment of type 2 diabetes.